What is the best course of treatment for a patient with a history of Clostridioides difficile (C. diff) infection who continues to experience diarrhea after completing a course of Dificid (fidaxomicin)?

Management of Ongoing Diarrhea After Completing Fidaxomicin for C. difficile Infection

The first critical step is to determine whether this represents true recurrent CDI versus an alternative diagnosis, as ongoing diarrhea after fidaxomicin may not be CDI recurrence—particularly if symptoms are atypical or unresponsive to standard therapy. 1, 2

Immediate Diagnostic Assessment

Before initiating additional CDI treatment, confirm the diagnosis:

• Verify clinical criteria: The patient must have ≥3 unformed stools in 24 hours with a positive C. difficile test (toxin or NAAT) to diagnose recurrent CDI 1, 3
• Rule out alternative causes: Consider post-infectious irritable bowel syndrome, inflammatory bowel disease flare, medication side effects, or other infections—especially if symptoms include diarrhea alternating with constipation or lack of response to vancomycin/fidaxomicin 1, 2
• Assess severity markers: Check WBC (severe if ≥15,000 cells/μL), serum creatinine (severe if ≥1.5 mg/dL), and lactate (fulminant if ≥5.0 mmol/L) 3, 2, 4
• Do NOT test for cure: PCR can remain positive for weeks despite clinical resolution, and testing asymptomatic patients is not recommended 2

Primary Recommendation: Fecal Microbiota-Based Therapy

If this represents confirmed recurrent CDI after fidaxomicin failure, fecal microbiota transplantation (FMT) is the treatment of choice, achieving 87-92% clinical resolution compared to 40-50% with additional antibiotic courses. 3, 2

FMT Implementation Details

• Timing: Administer FMT upon completion of a standard course of CDI antibiotics (vancomycin or fidaxomicin), not during active treatment 1, 3
• Bridging therapy: Use suppressive vancomycin to bridge until FMT is administered 1
• Antibiotic washout: Stop CDI antibiotics 1-3 days before conventional FMT (1 day if bowel purge given, 3 days without purge) 1
• Route of administration: Colonoscopy or flexible sigmoidoscopy is preferred for the first dose, allowing confirmation of diagnosis and severity assessment 3. Alternative routes include enema (80-100% success) or FDA-approved oral capsule formulations 1, 3
• Efficacy: First FMT infusion achieves 81% sustained resolution in randomized trials, with overall success rates of 80-100% via colonoscopy 3

Indications for FMT

FMT should be considered after:

• Second recurrence (third episode) of CDI 1, 2
• First recurrence in high-risk patients: Those who recovered from severe/fulminant CDI or have significant comorbidities 1, 3

Alternative: Extended-Pulsed Fidaxomicin or Vancomycin Taper

If FMT is not immediately available, contraindicated, or declined by the patient:

Option 1: Extended-Pulsed Fidaxomicin

• Dosing: Fidaxomicin 200 mg twice daily for 5 days, then once daily for 20 days 2
• Evidence: Demonstrates 70-80% sustained clinical response in recurrent CDI 2
• Consideration: This represents a different dosing strategy than the standard 10-day course already completed 5

Option 2: Vancomycin Tapered-and-Pulsed Regimen

• Dosing protocol: 3, 2
  • Vancomycin 125 mg every 6 hours for 10-14 days
  • Then 125 mg every 12 hours for 7 days
  • Then 125 mg every 24 hours for 7 days
  • Finally 125 mg every 48-72 hours for 2-8 weeks
• Rationale: Prolonged pulsed dosing allows gut microbiota recovery between doses 3

Option 3: Vancomycin Followed by Rifaximin

• Dosing: Standard vancomycin course followed by rifaximin 400 mg three times daily for 20 days 2
• Efficacy: 60-70% clinical response rate 2

Adjunctive Therapy: Bezlotoxumab

Consider adding bezlotoxumab 10 mg/kg as a single IV infusion during or shortly after antibiotic completion for patients at high risk of further recurrence. 1, 2

• High-risk criteria: History of CDI in past 6 months, immunocompromised state, age ≥65 years, severe CDI 1
• Evidence: Reduces CDI recurrence by 38% (RR 0.62; 95% CI 0.51-0.75) and hospital readmission by 54% (RR 0.46; 95% CI 0.29-0.71) 1
• Important caveat: Reserve for patients without congestive heart failure history, as FDA warns of increased risk in this population 1
• Limitation with fidaxomicin: Data on bezlotoxumab when fidaxomicin is the standard-of-care antibiotic are limited (<5% of trial participants) 1

Critical Supportive Measures

• Discontinue non-essential antibiotics immediately: Ongoing antibiotics may diminish efficacy of FMT and increase recurrence risk 1, 3, 2
• Stop proton pump inhibitors unless absolutely required, as they increase CDI recurrence risk 3, 2
• Avoid high-risk antibiotics: Clindamycin, third-generation cephalosporins, fluoroquinolones, and broad-spectrum penicillins 2
• Never use antimotility agents: Loperamide and opiates can precipitate toxic megacolon and worsen outcomes 2, 4

Monitoring for Severe or Fulminant Disease

Watch for warning signs requiring escalation to surgical consultation:

• Laboratory markers: WBC ≥25,000 cells/μL or rising, lactate ≥5.0 mmol/L, creatinine >1.5 mg/dL or rising 3, 2
• Clinical signs: Ileus, toxic megacolon, peritoneal signs, hemodynamic instability 3, 2, 4
• Fulminant CDI management: Requires vancomycin 500 mg orally four times daily plus rectal vancomycin 500 mg in 100 mL normal saline every 6 hours if ileus present 4

Special Populations

Immunocompromised Patients

• Mildly/moderately immunocompromised: FMT appears safe based on retrospective data 3
• Severely immunocompromised: Avoid FMT (patients on active cytotoxic therapy, recent stem cell transplant) 1
• Bezlotoxumab: May be particularly beneficial in immunocompromised patients 3

Patients Requiring Frequent Antibiotics

• Careful consideration needed: Ongoing antibiotics may diminish FMT efficacy 1
• Alternative: Extended vancomycin taper may be more appropriate 1

Common Pitfalls to Avoid

• Testing for cure: Never retest asymptomatic patients, as molecular tests remain positive for weeks despite clinical resolution 2
• Assuming all diarrhea is CDI: Alternative diagnoses are common, especially with atypical symptoms 1, 2
• Using metronidazole for recurrent CDI: Metronidazole is inferior to vancomycin/fidaxomicin and should not be used for recurrent episodes 4
• Delaying FMT: After multiple recurrences, FMT has superior efficacy to additional antibiotic courses 3, 2